Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia.
Biomolecules. 2021 Jan 4;11(1):54. doi: 10.3390/biom11010054.
Protein homeostasis, or proteostasis, is crucial for the functioning of a cell, as proteins that are mislocalized, present in excessive amounts, or aberrant due to misfolding or other type of damage can be harmful. Proteostasis includes attaining the correct protein structure, localization, and the formation of higher order complexes, and well as the appropriate protein concentrations. Consequences of proteostasis imbalance are evident in a range of neurodegenerative diseases characterized by protein misfolding and aggregation, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. To protect the cell from the accumulation of aberrant proteins, a network of protein quality control (PQC) pathways identifies the substrates and direct them towards refolding or elimination via regulated protein degradation. The main pathway for degradation of misfolded proteins is the ubiquitin-proteasome system. PQC pathways have been first described in the cytoplasm and the endoplasmic reticulum, however, accumulating evidence indicates that the nucleus is an important PQC compartment for ubiquitination and proteasomal degradation of not only nuclear, but also cytoplasmic proteins. In this review, we summarize the nuclear ubiquitin-proteasome pathways involved in proteostasis maintenance in yeast, focusing on inner nuclear membrane-associated degradation (INMAD) and San1-mediated protein quality control.
蛋白质动态平衡，又称蛋白稳态，对细胞功能至关重要，因为定位错误、过量存在、错误折叠或其他类型损伤的异常蛋白可能是有害的。蛋白稳态包括获得正确的蛋白结构、定位和形成更高阶的复合物，以及适当的蛋白浓度。蛋白动态平衡失衡的后果在一系列以蛋白错误折叠和聚集为特征的神经退行性疾病中显而易见，如阿尔茨海默病、帕金森病和肌萎缩性侧索硬化症。为了防止细胞内异常蛋白的积累，蛋白质量控制系统（PQC）网络会识别底物，并通过调控蛋白降解将其定向重折叠或清除。错误折叠蛋白的主要降解途径是泛素-蛋白酶体系统。最初在细胞质和内质网中描述了 PQC 途径，但越来越多的证据表明，细胞核是一个重要的 PQC 隔室，不仅可以对核蛋白，还可以对细胞质蛋白进行泛素化和蛋白酶体降解。在这篇综述中，我们总结了酵母中参与蛋白稳态维持的核泛素-蛋白酶体途径，重点介绍了核内膜相关降解（INMAD）和 San1 介导的蛋白质量控制。
